When one speaks of neurotropic viruses he generally has in mind the
arthropod-borne encephalitides, poliomyelitis, and rabies. However, the
neurotropic virus group is generally extended to include many other viruses
which affect the central nervous system, for example, agents of lymphocytic
choriomeningitis, mumps, the Coxsackie group, and the agents from mosquitoes
and patients of the equatorial areas of Africa and South America; this
last group has, in our patois, come to be known as the "tropical group"
of viruses.

It should be mentioned at once that the two neurotropic virus diseases
of importance in the Korean conflict were Japanese encephalitis and poliomyelitis.
The total numbers of cases occurring in American troops in Korea during
the years 1950-1953 were not great, 402 of encephalitis and 120 of paralytic
poliomyelitis.

At the beginning of World War II the subject of Japanese encephalitis
was one which caused much worry to those concerned with maintaining the
health of American troops in case they should enter the areas where this
disease was endemic. One had only to recall the great epidemics in Japan
and the complete susceptibility of Americans to this virus which does not
exist in the Western Hemisphere to understand the reasons for such worry.
The theme of this report is to de-emphasize to some extent the military
importance of Japanese encephalitis. However, it should be pointed out
at once that the basis for de-emphasis has developed since the end of World
War II. Moreover, we should continue to respect the judgment and admire
the work of those who contributed so much to our knowledge and preparedness
in this field during World War II.

Incidence of Japanese Encephalitis

The number of cases of encephalitis in civilian populations of Japan,
Korea, and Okinawa in certain years since 1924 are indicated in table 1.
Epidemic encephalitis has been recognized as a clinical entity in Japan
at least since 1924 (1). Subsequently, epidemics were recognized
in

*Presented 28 April
1954, to the Course on Recent Advances in Medicine and Surgery, Army Medical
Service Graduate School, Walter Reed Army Medical Center, Washington,
D. C.

220

Table 1. Number of Cases of Encephalitis in
Civilian Populations of Okinawa, Korea, and Japan from 1924-52

Year

Number of cases of encephalitis in civilians of-

Japan (population 75,000,000)

Korea (population 20,000,000)

Okinawa (population 500,000)

1924

6,125

(*)

-----

1935

5,370

-----

-----

1946

150

-----

32

1947

259

-----

196

1948

7,208

-----

47

1949

1,294

5,548

35

1950

5,182

-----

31

1951

2,152

Rare

45

1952

711

-----

-----

*Designates data not known.

this population yearly with incidences ranging from 150 cases up to
over 7,000 cases (1-3). The disease was recognized in Korea at least
in 1949 (4); however, the mass movement of civilian residents has
precluded any reliable data during the years of the Korean conflict except
that the incidence of encephalitis in Korea, 1951, was considered rare
(2). Encephalitis on Okinawa has been studied extensively by American
personnel, yielding data (2, 5, 6) more reliable than the other
data presented, since most statistical data are compilations made through
native public health organizations.

The actual experience of the American troops with encephalitis is epitomized
in table 2 which summarizes the annual incidence of encephalitis in American
personnel in the Far East (5-8) and also

Table 2. Number of Cases of Encephalitis in
Military Forces, Their Dependents, and Department of the Army Civilians
in Various Areas of the FECOM

Year

Number of cases of encephalitis

Proved Japanese encephalitis FECOM

Japan

Korea

Okinawa

FECOM

1946

0

4

0

4

4

1947

23

2

2

27

2

1948

23

0

16

39

31

1949

17

0

17

34

13

1950

26

299

17

342

201

1951

11

21

16

48

7

1952

65

36

17

118

30

1953

53

46

29

128

10

221

indicates the number of cases which were proved to be caused by Japanese
encephalitis virus. Such proof was obtained at the 406th Medical General
Laboratory and consisted of isolation of the virus from autopsy or clinical
materials or demonstration of specific antibodies in the sera of convalescent
patients.

The figures for 1950 are of particular importance since they include
the outbreak during the late summer and early fall in our troops who were
then compressed into the Pusan perimeter (6). Colonel Long will
report the details of this episode later in this symposium, hence no more
will be said about it now. It is worth pointing out that, during 1950,
when the vast majority of cases of encephalitis in the Far East Command
consisted of cases from the Korean epidemic, about two-thirds of the patients
were proved to have been infected with the virus of Japanese encephalitis.
Since then a progressively smaller proportion of the cases with a clinical
diagnosis of encephalitis have been caused by Japanese virus. This matter
cannot be explained on the basis of inadequate laboratory methods since
the armamentarium of technics has been constantly improving in recent years.
It is suggested that this change is connected with such factors as the
increasing awareness of clinicians regarding the diagnosis of central nervous
system infections and their tendency at times to include patients with
aseptic meningitis in the group of encephalitides. Many of the paired sera
have been tested in the usual battery of diagnostic procedures employed
at the 406th Medical General Laboratory and the Army Medical Service Graduate
School (3) without throwing light on the etiology.

Japanese Encephalitis Vaccine

An important decision regarding vaccination against Japanese encephalitis
was made during the Korean conflict. Therefore, it is appropriate to review
the background for the decision and to estimate its effects.

Vaccination against Japanese encephalitis had been practiced by the
Russians since 1941 (9), and in the United States a formalinized
mouse brain vaccine was developed by Sabin and others for trials in the
U. S. Army (10). This mouse brain vaccine was safe and potent as
judged by laboratory tests (10). Inoculation of over 250,000 persons
on Okinawa with this type of vaccine in 1945 and 1946 (11) did not
provide sufficient data to draw a firm conclusion as to its efficacy in
engendering immunity to Japanese encephalitis. Dr. Sabin claimed that no
case of demyelinating encephalitis occurred in these vaccinated troops.
However, he noted three cases of polyneuritis (one fatal) in this vaccinated
group but also pointed out that patients with the same signs were present
during this period in non-vaccinated troops.

222

In 1945 and 1946, commercially prepared mouse brain vaccine was used
in the Far Eastern Theater (12). The new chick-embryo-type Japanese
encephalitis vaccine was introduced into the Far East in 1946 (12),
when, in this year and in 1947, the Army Medical Service Graduate School
supplied over 800,000 ml. of mouse brain vaccine. These vaccines were effective
in protecting mice against challenge with Japanese encephalitis virus and
in eliciting neutralizing antibodies in 60 percent of human volunteers
inoculated under controlled conditions. Routine immunization of all troops
in the Far East Command with the chick embryo vaccine was adopted in 1948
and continued until the fall of 1951.

Of 11,338 persons inoculated with Japanese encephalitis chick embryo
vaccine, on whom observations were made in the Far East and the records
forwarded to The Surgeon General's Office, eight developed reactions of
an allergic nature. Three of these were classed as severe and anaphylactic
in nature with onset varying from 20 minutes to 24 hours after administration
of vaccine. The other five had moderate reactions characterized by fever
and urticaria. There were no fatalities (13).

Trials of the vaccine were also made in civilians and those trials in
Okayama, Japan, offered the most complete results (6). In 1946 over
14,000 children in Okayama received three inoculations of commercially
prepared mouse brain vaccine and in 1948 and 1949 almost 40,000 additional
children were vaccinated in the same manner with the standard Army chick
embryo vaccine. After the initial series of inoculations each child was
revaccinated yearly until 1950 with one stimulating dose of the chick embryo
vaccine. Thus, during the period 1946-1949, over 50,000 children between
5 and 10 years of age were vaccinated, leaving other children unvaccinated.

This population was observed yearly and the results (quoted from Dr.
Sabin's report to the Virus and Rickettsial Commission, Armed Forces Epidemiological
Board) (14) were as follows: ". . . the incidence of the disease
in the unvaccinated group turned out to be much less than was anticipated.
The evaluation of the results is further less than was anticipated. The
evaluation of the results is further complicated by the fact that only
a varying and sometimes small proportion of the clinically diagnosed cases
were studied serologically. Nevertheless, during the years of 1948 and
1949, when chick embryo vaccine was administered and a sufficient number
of clinically diagnosed cases occurred in the group under investigation,
the incidence was 7.6 and 9.2 times higher in the unvaccinated than in
the vaccinated group. While the data are not statistically significant
for any one year, they do achieve such significance when the results for
the years 1947 to 1949 are combined. Even in 1950, when no vaccine was
admin-

223

istered but a residual effect from the previous years might still have
been in operation the incidence was 4.6 times greater in the unvaccinated
group. It should be noted that cases, not all confirmed, occurred among
the vaccinated, but the incidence was at all times greater among the unvaccinated.
However, these results cannot be completely transposed to individuals of
Army age, since it has been found that the same dosage of vaccine gives
rise to a higher incidence of neutralizing antibodies in children than
in adults . . . ."

The value of the vaccine in protecting U. S. troops was more difficult
to judge. This was due to the lack of control of unvaccinated troops, their
rapid movements, and the lack of complete individual immunization records.
Using those data available, however, a reconsideration of the value of
this vaccine was made by certain members of the Virus and Rickettsial Disease
Commission, Armed Forces Epidemiological Board, in the fall of 1951. Briefly,
the considered opinion (15) was:

There is some evidence that the annual administration of this vaccine
to Japanese children has lowered the incidence of clinically reported cases
in Okayama prefecture (in Japan).

The evidence so far fails to indicate that vaccination of the U. S.
troops in Japan and Korea has been effective as a prophylactic measure.
No controlled studies have been made in American troops and the data collected
have not proved conclusively that the vaccine is worthless. It appears,
however, that the vaccine is of dubious value as a prophylactic measure
for the protection of troops.

On the basis of these recommendations, the commercial production of
Japanese encephalitis vaccine was stopped and the Adjutant General ordered
that, "effective with the 1952 season," routine vaccination of
personnel in the Far East Command with Japanese encephalitis vaccine cease
(16).

The failure of the vaccine has been attributed by some to low potency
and lack of stability. At the present time no vaccine is available for
routine vaccination of military personnel against Japanese encephalitis
but a search is still being carried out at the Army Medical Service Graduate
School for a safe, potent and stable immunizing material to be used against
this disease. To achieve this, various procedures have been attempted without
yielding any preparation with advantages over formalinized mouse brain
vaccine, already used in the field. The procedures have included investigations
of various methods of inactivation of Japanese encephalitis virus such
as the use of ethylene oxide, acetone, high-speed cathode rays, ultraviolet
light, ultrasonic vibration, and various levels of formaldehyde (17);
various methods of purification using protamine sulfate, norite, cellite,
or

224

attaclay (17); attempts to obtain higher titers of virus to use
in a vaccine (17); and attempts to attenuate the infectivity of
the virus for use as a live virus vaccine (17). At the present time
a satisfactory immunizing agent against Japanese encephalitis is considered
highly desirable.

Recent Research on Japanese Encephalitis

Most of the recent advances concerning Japanese encephalitis have been
in its ecology and this approach has been most fruitfully pursued at the
406th Medical General Laboratory in Tokyo (2, 3, 6). It had already
been found by them that Japanese encephalitis epidemics occurred at the
same time as the Culex tritaenorrhynchus mosquito population peak;
moreover, without this peak, epidemics did not occur. Even with this information
it was not known how the mosquito became infected and potentiated the virus
during inter-epidemic seasons. Investigations on the ecology of this disease
in Japan revealed that certain migrating fowl also experienced infection
with Japanese encephalitis virus and the mosquitoes associated with them
were found to contain active virus but at approximately the same time that
epidemics occurred in man. This does not indicate that the fowl is a reservoir
of infection but indicates that it may be vitally concerned in the potentiation
of the epidemic, once started. It should be mentioned that viral infections
had previously been diagnosed in animals in Japan (18) when no visible
epidemic was occurring in human beings in the same locality.

The use of hemagglutination-inhibition procedures for demonstration
of antibodies to Japanese encephalitis as well as to certain other arthropod-borne
viral diseases has been described in the literature (19, 20) and
offers hope as an additional diagnostic tool. Although much experience
needs to be obtained with any new diagnostic tool in order for it to be
of value and to establish suitable criteria for its use as a routine diagnostic
aid, this procedure is being evaluated at the present time in Japan (3).
In conjunction with the complement-fixation test and neutralization test
it may form part of a widely varied armamentarium of available diagnostic
tests.

At the time of the Korean conflict, studies on Japanese encephalitis
were proceeding in other geographical locations: in 1951, a U. S. Army
Medical Research Team, in conjunction with British scientists, isolated
a virus from a fatal case of encephalitis in Malaya which was later identified
as Japanese encephalitis virus (21). Subsequently other isolations
of this same virus were made by British investigators in Malaya (22,
23).

225

Serological studies carried out by the Japanese in World War II (24)
and by the U. S. Army Medical Research Team in 1951 (25) indicated
that 75 percent of the Malayan indigenous population tested had evidence
of past infection with Japanese encephalitis virus. Also most pigs, bovines,
equines, and dogs showed evidence of past infection. This is in no way
different from serological studies carried out in Japan (18, 26)
but epidemic encephalitis has been reported very rarely in Southeast Asia
(25). The lack of outbreaks is thought to be due to the possible
presence of arthropod vectors throughout the year in this tropical region
but this does not explain the quantitative lack of clinical cases one would
expect in a population where Japanese encephalitis virus is continually
present. A semi-permanent U. S. Army laboratory was established in 1953
at the Institute for Medical Research, Kuala Lumpur, Malaya, and there
further studies on the ecology of Japanese encephalitis as well as other
arthropod-borne viral diseases are being carried out.

Using published results in which neutralizing antibodies to Japanese
encephalitis in man and animals have been described, Japanese encephalitis
virus has been isolated and identified, or cases of Japanese encephalitis
have been proved, a chart of the probable distribution of Japanese encephalitis
in the world has been constructed as figure 1. Although the zones of Japanese
encephalitis incidence appear dispersed, as exemplified by serological
survey results in the cities of Kirin, Tientsin and others, it would seem
logical from the data to consider Japanese encephalitis present, not as
foci, but as a broad endemic band in all of Eastern Asia (4, 7, 9, 21,
22, 24, 25, 27, 32), at least as far north as the Maritime District
of Siberia and extending south well into the East Indies, possibly even
into New Guinea and Australia. This band would include the islands off
the coast of Asia; of Japan (1, 26), Okinawa (5, 11, 28),
Formosa (24, 33), Guam (34), the Philippine Islands (24,
35, 36), and Borneo (25). Moreover, it is believed on the basis
of serological surveys that the disease extends to the westward in Southern
Asia at least as far as India (37); antibodies to this virus were
even reported at one time in the sera of African residents (38).
However, in certain of these areas, notably Africa, where serological surveys
indicate that West Nile virus is present, such data must now be interpreted
with some caution; since an antigenic relationship is known to exist between
West Nile and Japanese virus, and may exist between other "tropical
viruses" and the Japanese encephalitis virus (39).

In 1951 an epidemic of encephalitis occurred in Australia and from this
outbreak an infective agent was isolated (40) and identified as
a newly recognized arthropod-borne virus called Murray Valley encephalitis
virus, closely related antigenically to Japanese encepha-

litis virus (41). Its distribution and importance outside Australia
are not known. However, because of its very close antigenic relationship
to Japanese encephalitis virus it could logically be considered a variant
of Japanese encephalitis virus in the same way as influenza A´ is
a variant of influenza A. Interesting speculations have been published
that this newly discovered virus disease is a recurrence of Australian
X disease last seen in Australia in 1925 (42). Its distribution
in Australia, and possibly in New Guinea (43), is indicated also
in figure 1 in lighter shading. It should be pointed out that the limits
of the endemic Japanese encephalitis areas, as represented on this map,
are delineated not by evidence of the lack of disease but by our ignorance.

Russian Spring-Summer Encephalitis

Russian spring-summer encephalitis (RSSE), a tick-borne disease, was
not observed in any American troops in the Far East nor has

227

any report been received of RSSE in our troops in Korea. Louping ill
(LI), serologically similar (44) and even indistinguishable (45)
from RSSE, is a cause of epizootics in sheep in the British Islands but
the relationship of these epizootics to the epidemics of RSSE is not clearly
understood. The probable geographic distribution of RSSE and LI is indicated
in figure 2.

It is unfortunate that we do not have more accurate data on the distribution
of this important disease. However, language barriers as well as the lack
of published experimental data require us to form only general conclusions
as to the location of those zones in the Soviet Union where RSSE has existed
and may now exist. RSSE is predominantly a disease of the U. S. S. R. (1)
extending from the steppes of Russia in East Siberia to continental Europe
where the disease has been recognized in West Russia. Outbreaks have been
reported recently from Central Europe; in Czechoslovakia (46), as
well as in Austria and Slovenia. (47). Here it is termed by some
workers as Central European encephalitis. Louping ill exists predominantly
in the British Islands where it has been endemic for over a century and
only a few cases of human infection under natural conditions have been
reported from the area representing the LI distribution (48-50).

Neutralizing antibodies to RSSE virus were found in the sera of a few
inhabitants of India (37) but as yet such antibodies have not been
reported in Southeast Asia, Japan or Korea (24). Its presence in
Khabarovsk, in the eastern Maritime Province of Siberia, was dangerously
close to the area of combat during the Korean conflict. This severe neurotropic
virus disease, as judged by morbidity, case fatality rate and presence
of residual signs, has not yet been recognized in Korea nor have neutralizing
antibodies to this virus been demonstrated in small numbers of sera tested
from Japanese nationals (17) and Okinawan natives (5).

Russian spring-summer encephalitis mouse brain vaccine used for vaccinating
laboratory personnel working with this virus has been satisfactory for
eliciting neutralizing antibody responses in these individuals and for
protecting mice against subsequent challenge with RSSE viruses. In the
hands of the Russians, the vaccine was reported to decrease the rate of
infection in Siberian residents (1). It appears, however, that this
vaccine cannot be lyophilized without losing large amounts of antigenicity
(17). Therefore, it must be left in the wet state under refrigeration
and under these conditions it becomes antigenically unsatisfactory within
60 to 90 days (17, 27).

Other Arthropod-borne Virus Diseases, Rabies and Poliomyelitis

In the years preceding and during the Korean conflict, St. Louis encephalitis,
Western equine encephalomyelitis and Venezuelan equine

encephalomyelitis were reported only in the Western Hemisphere. However,
Eastern equine encephalomyelitis, another disease of the Americas, was
recognized in the Philippine Islands (51).

Although rabies never became a serious problem in the Far East Command
and only one human case was recorded in U. S. troops (6), nevertheless,
laboratory facilities were frequently employed in the Far East on diagnostic
work on specimens submitted from animals suspected of having rabies. During
this period, ideas regarding prophylaxis against this disease in exposed
human beings, guided by the recommendations of investigators in this field
(52), swung toward administration of immune serum coupled with fewer
doses of the standard rabies vaccine. As yet, the use of this method in
the Army is reserved for those persons experiencing possible accidental
infection with rabies in the laboratory. Although there are other worth-while
recent advances in the prophylaxis against this disease, such as the World
Health Organization sponsored field use of the avian adapted Flury vaccine
in dogs (53), these had little or no effect on the practice of medicine
in Japan and Korea during the period of the Korean conflict.

Table 3. Number of Cases of Paralytic Poliomyelitis
in Military Forces, Their Dependents, and Department of the Army Civilians
in Various Areas of the FECOM During the Korean Conflict

Year

Number of cases of poliomyelitis

Japan

Korea

Okinawa

FECOM

1950

19

10

0

29

1951

4

21

1

26

1952

34

25

3

62

1953

30

64

24

118

Clinically diagnosed paralytic poliomyelitis accounted for about one-fourth
as many cases of central nervous system infection (3, 8) during
this period as did infectious encephalitis (table 3). The technical difficulties
in laboratory diagnosis of poliomyelitis are only now being resolved; hence,
little has been done among troops in the Far East regarding laboratory
proof of inapparent infection and non-paralytic disease caused by the three
antigenic types of poliomyelitis virus. Nevertheless, these forms of the
infection undoubtedly are fairly common in such personnel as they are in
any group with a high proportion of susceptibles that live in contact with
relatively unsanitary populations in which poliomyelitis virus circulates
freely. In one group of 18 soldiers in Japan who were diagnosed clinically
in

230

1946 as having aseptic meningitis, 2 were shown by laboratory studies
to have suffered an infection with poliomyelitis virus (54).

No isolation of Coxsackie agents was reported from the military forces
in the Far East Command during the Korean War. However, the members of
this ubiquitous group have become so numerous and their identification
so cumbersome that routine diagnosis is usually avoided.

Lymphocytic choriomeningitis was not reported as a cause of disease
in the Far East Command during or just preceeding the Korean conflict.
Moreover, materials from 47 cases of aseptic meningitis from this theater
were studied in the laboratory for evidence of infection with the agent,
with negative results (3). However, with the wide geographic distribution
of lymphocytic choriomeningitis virus in mice, it would be presumptuous
to conclude that this disease has never occurred in troops of the Far East
Command.

We should not close this discussion without mentioning that group of
heterogeneous agents conveniently called the "tropical viruses."
These viruses, isolated in Africa or South America, sometimes from man
but usually from mosquitoes, produce a fulminating encephalitis in mice
when inoculated intracerebrally, but the nature of most of the diseases
caused by these viruses under natural conditions is yet unknown. They are,
no doubt, arthropod-borne viruses but whether in man most of them are neurotropic
in character remains to be determined. Much effort is being expanded currently
by groups from the Rockefeller Foundation and the Army Medical Service
Graduate School to determine the distribution of these viruses in the world
and their importance as causes of diseases in man. These agents include:
Semliki (55), Uganda S (56), Ntaya (57), Anopheles
A (58), Anopheles B (58), Wyeomyia (58), Zika (59),
Ilheus (60), West Nile (61), Bunyamwera (62), Mengo
(63), and Bwamba, (64).

No discussion of neurotropic viruses in Northeast Asia could neglect
to mention at this time (April 1954) the additional available information
on the occurrence of arthropod-borne viral agents in Southeast Asia, particularly
Indochina. Recent, and as yet unpublished, serological surveys undertaken
in our laboratory in collaboration with other groups of workers, as well
as other recently published results (65) indicate that infections
with Zika, Ntaya, Ilheus, and Dengue I and II viruses are almost as frequent
in the population of Malaya as is that with Japanese encephalitis virus.
Furthermore, Semliki Forest and Uganda S agents have left a few antibody
trails in this area but Anopheles A and B, Bunyamwera, Bwamba and Wyeomyia
have not. Little is known about the occurrence of these agents in the more
northerly parts of Southeast Asia; however, the flora and fauna of much
of this general region are similar and one would anticipate that

231

the viruses of Malaya spread beyond its geographic boundaries. Japanese
encephalitis virus, at least, is found in Indochina and Burma; during World
War II Japanese investigators found antibodies against this agent in 44
percent of the native peoples of Hanoi and in 52 percent of the horses
in Burma (24).

Conclusions

What new things have we learned about the neurotropic viruses as military
problems from the Korean experience? The following statements answer the
question in part at least.

1. Japanese encephalitis has not yet been brought under adequate control
in armies in the field by either immunization or mosquito control measures.
Additional work is indicated in preventive measures.

2. Despite this, Japanese encephalitis has not turned out to be the
awe-inspiring epidemic disease which the Americans in 1942 thought it might
prove to be, when susceptible populations were brought into endemic areas.
Four hundred and two cases of encephalitis occurred in American military
forces in Korea during the years 1950 to 1953 and about half of these were
proved to be caused by Japanese encephalitis virus.

3. Paralytic poliomyelitis was the second most important neurotropic
virus disease among troops in Korea with 120 cases occurring over the period
1950-53. With the increasing numbers of susceptibles (no neutralizing antibodies
against one or more of the three types of poliomyelitis virus) among young
American adults, poliomyelitis can be expected to be an increasing problem
among troops maintained under unsanitary conditions or in contact with
foreigners with unsuitable habits.

4. Other neurotropic viral diseases were of relatively little importance
during the Korean conflict. No evidence of infection with Russian spring-summer
encephalitis virus has been encountered in our forces in Korea. Fifty to
a hundred sporadic cases of central nervous system disease in which a viral
etiology was suspected occurred in the Far East annually from 1950 to 1953,
but the responsible etiological agents in most instances remained undetermined,
a finding also common in other geographic areas.